Atorvastatin is safe and may reduce the risk of cardiovascular events, compared with placebo, among patients with rheumatoid arthritis (RA), according to data published online today in Arthritis and Rheumatology.
However, the randomized Trial of Atorvastatin for the primary prevention of Cardiovascular Events in patients with Rheumatoid Arthritis (TRACE RA) did not proceed as planned, and the primary endpoint of risk reduction was not significantly different between the active drug and placebo groups.
The trial was intended to enroll 5400 patients who would be followed for 5 years. As designed, the trial would have been able to detect a 32% risk reduction with atorvastatin based on a 1.8% annual event rate.
However, the annual rate of cardiovascular events (CVE) in the study population turned out to be lower than anticipated, at just 0.77%.
“The unexpectedly low event rate and resulting limited statistical power to detect an effect during the planned five years of follow-up led to premature termination of the trial” after inclusion of only 3002 patients, write George D. Kitas, MD, PhD, from Russells Hall Hospital, Dudley, United Kingdom, and colleagues.
The authors conclude that the study, as conducted, suggests contemporary patients with RA are likely to experience the same degree of benefit from statin therapy as other populations do. However, the low rate of cardiovascular events indicates that a substantial group of patients with RA already have a relatively low cardiovascular disease (CVD) risk.
Patients with RA continue to experience greater mortality rates than the general population does, in part because of an increased risk of CVD. Yet, the benefit of statins in RA has not yet been established in this population.
With this in mind, Kitas and colleagues conducted TRACE RA, a randomized, double-blind, placebo-controlled trial across 102 rheumatology centers in the UK.
The trial enrolled patients who fulfilled the 1987 American College of Rheumatology criteria, and who were at least 50 years old or had suffered from RA for at least 10 years. To be eligible, patients had to have been on stable RA therapy for at least the 3 months before the study began.
The primary endpoint was major cardiovascular events, defined as nonfatal myocardial infarction (MI), nonfatal presumed ischemic stroke, transient ischemic attack (TIA), any coronary or noncoronary revascularization, or cardiovascular death (excluding confirmed cerebral hemorrhage and noncoronary cardiac death), during the scheduled treatment period.
The researchers randomly assigned 3002 patients to receive atorvastatin 40 mg (1504 patients) or placebo (1498 patients) and followed them for a median of 2.5 years, not the planned 5 years.
Cardiovascular events occurred in 24 patients (1.6%) receiving atorvastatin, compared with 36 (2.4%) of those receiving placebo (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.39 – 1.11; P = .115). After adjustments for baseline factors, study location, and off-protocol statin use, the HR was 0.60 (95% CI, 0.32 – 1.15), but the difference was not statistically significant (P = .127).
At the end of the trial, low-density lipoprotein-cholesterol (LDL-C) levels were significantly lower among patients in the atorvastatin group than in those in the placebo group at 2.21 mmol/L vs 2.98 mmol/L (P < .0001).
According to the authors, this translated to a CVE risk reduction per 1 mmol/L LDL-C of 42% (95% CI, -14% to 70%), similar to what has been reported in studies using statin treatment in non-RA populations.
The rates of adverse events were similar between the atorvastatin (19.8%) and placebo (19.5%) groups, and the authors say no unexpected serious adverse reactions occurred.
Because of the trial’s early termination, the authors were not surprised that the HR for the primary endpoint was not significant. “The results for the primary outcome are therefore best represented as the estimated hazard ratio and its associated confidence interval,” Kitas and colleagues write.
“[T]his does not support prescribing statins to all RA patients, one of the main questions addressed by this trial,” the authors conclude. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk,” in accordance with guideline recommendation for managing cardiovascular risk in the general population.
In an accompanying editorial, Katherine P. Liao, MD, and Daniel H. Solomon, MD, both from Harvard Medical School, Boston, Massachusetts, commend the researchers for conducting the first trial among patients with RA designed to study hard CVD endpoints.
“While we believe the broad inclusion criteria for TRACE-RA were appropriate, the results suggest that we need better methods for identifying the appropriate patient population in RA to target for CV risk reduction strategies,” they note.
Nevertheless, Liao and Solomon emphasize that the results of this trial provide information that will be useful for researchers and clinicians managing CVD risk among not just patients with RA, but also among those with other rheumatic diseases.
This study was supported by Arthritis Research UK and British Heart Foundation. Pfizer UK provided atorvastatin and matching placebo for the study, along with unrestricted grants for establishing a TRACE RA biobank. Pfizer provided a nonvoting observer to the Trial Steering Committee. Multiple authors have reported the following: receiving honoraria for lectures from, participating in advisory boards for, and/or receiving hospitality from Roche, AbbVie, Pfizer, Novartis, UCB, Bristol-Myers Squibb , and GlaxoSmithKline; receiving grant support from AstraZeneca, Boehringer Ingelheim, or Eli Lilly; and consulting for Amgen, Sanofi, Boehringer Ingelheim, Janssen, Novo Nordisk, Eli Lilly, Bayer, Rexgenero, and Astra Zeneca. One editorialist has reported receiving salary support through research contracts from AbbVie, Amgen, Corrona, Genentech, Janssen, and Pfizer. Two authors and one editorialist disclosed no relevant financial relationships.